Photobiomodulation Therapy for Muscular Dystrophy: Time for a Trial?

Muscular dystrophy (MD) describes a group of about 30 different genetic diseases characterized by progressive weakness in skeletal muscles, followed by muscle necrosis and wasting, often followed by an early death (20–40 years of age). ¹ Of these 30 variants, the most common (about 50% prevalence) is Duchenne muscular dystrophy (DMD), an X-linked recessive disorder that primarily affects males. DMD was named after the French neurologist Guillaume Benjamin Amand Duchenne (1806–1875) who described the details of a case in the 1860s. DMD is quite rare affecting only 1 in 5000 male births, and 1 in 50,000 female births. The genetic mutations responsible are in the gene coding for the dystrophin protein located on chromosome Xp21. The dystrophin protein connects the actin cytoskeleton of the muscle cells to the extracellular matrix by passing through the sarcolemma (specialized plasma membrane of muscle cells).

The DMD mutations can be deletions, duplications, or point mutations, but the net result is a large drop in the amount of functional protein produced. The lack of functional dystrophin allows extracellular calcium to penetrate through the sarcolemma into the cells and then accumulate in the mitochondria. The resulting mitochondrial dysfunction causes the generation of reactive oxygen species (ROS), which then causes additional mitochondrial dysfunction in a self-amplifying cascade and eventually leads to widespread cell death. There is also a risk of rhabdomyolysis, which is a life-threatening condition caused by rapid muscle destruction.

Other variants of MD include Becker MD, congenital MD, myotonic MD, limb-girdle MD, facioscapulohumeral MD, Emery–Dreifuss MD, oculopharyngeal MD, and distal MD in decreasing order of prevalence. The genetic causes are different for different types of MD, while some variants are X-linked, others are not, and some are not actually inherited but are de novo mutations.

The traditional available treatments for DMD are rather disappointing overall, consisting of corticosteroids, antioxidant supplements, and supportive measures as the disease progresses. However, recently there has been an explosion in the use of gene-based and antisense treatments for DMD. The monogenic nature of the disease etiology has made DMD an attractive target for nucleic acid-based therapies. The most advanced of these is the use of antisense oligonucleotides that bind to specific parts of the gene to allow “exon skipping,” and can lead to the production of some functional dystrophin protein. Two of these exon-skipping approaches (eteplirsen and golodirsen) are being tested in clinical trials. Other approaches at various stages of development include microdystrophin therapy, stop codon readthrough therapy, CRISPR-based gene editing, cell-based therapy, and utrophin upregulation. ²

Nevertheless, these gene-based therapies will take some time to gain regulatory approval (if ever) and to make a real difference to those afflicted with this disease. Therefore, it is worth considering whether photobiomodulation therapy (PBMT) could be beneficial at the present time. There are several theoretical considerations and preclinical animal studies that suggest that this could indeed be the case.

PBMT is known to act primarily on the mitochondria. ³ The red/near infrared light is absorbed by chromophores of the respiratory chain located in the inner mitochondrial membrane, where it increases mitochondrial membrane potential (MMP), oxygen consumption, and adenosine triphosphate (ATP) production. When the MMP is increased in the dysfunctional mitochondria, it results in a reduction in the ROS production caused by defective electron transport, while in normal mitochondria, there is a brief and limited increase in ROS, which could induce some protective responses based on antioxidant enzymes. The effect of PBMT on the mitochondria is to switch the metabolism away from glycolysis and toward oxidative phosphorylation (OXPHOS).

This switch has two major consequences. One is that proinflammatory macrophages with the M1 phenotype carry out glycolysis, while anti-inflammatory M2 macrophages rely more on OXPHOS. This change in macrophage phenotype accounts for the pronounced anti-inflammatory effects of PBMT. The second consequence is that the stem cells located in their hypoxic niche must carry out glycolysis, but when their metabolism is switched to OXPHOS, they leave their niche in search of oxygen, where they can respond to biological cues and then differentiate into tissue repairing cells. Moreover, the changes in mitochondria produced by PBMT can stimulate the process of mitogenesis (creation of new healthy mitochondria) and the upregulation of antiapoptotic proteins (BCL-2 and survivin), thus preventing cell death. In addition, PBMT in vitro can produce major changes in intracellular calcium and alter its subcellular localization.

When one considers the most important pathological mechanisms responsible for the muscle damage occurring in DMD, it could be expected that PBMT could have multiple beneficial effects. The stimulation of mitochondrial metabolism and mitogenesis will particularly benefit muscles, which are highly dependent on mitochondrial activity and a sufficient supply of ATP compared to some other tissues. The reduction in apoptosis will lessen or prevent widespread cell death from occurring inside the muscles. The anti-inflammatory effects of PBMT will be helpful in DMD, which is often treated with corticosteroids for reducing excessive inflammation. The antioxidant effects of PBMT will help prevent the oxidative stress involved in the severe muscle damage caused by DMD.

The changes in intracellular calcium produced by PBMT could also modulate calcium transport inside the muscles. The ability of PBMT to stimulate stem cells is highly relevant because the specialized satellite cells present in skeletal muscles function as stem or progenitor cells. ⁴ These mononucleated cells are located between the sarcolemma and the basement membrane, and are responsible for the well-known ability of muscles to grow and proliferate in response to exercise training.

There have been many published reports describing the remarkable ability of PBMT to benefit skeletal muscles in healthy individuals, athletes undergoing exercise training, delayed onset muscle soreness after strenuous exercise, and in patients with muscle strains and tears. ^5,6 In fact, PBM devices based on light-emitting diode (LED) arrays or whole body light beds are now almost indispensible in major sports teams and training facilities.

Researchers in DMD have relied heavily on a laboratory mouse model of the disease, called mdx mice. ⁷ These mice were discovered in the early 1980s in a colony of C57BL/10ScSn mice with elevated serum creatine kinase and histological evidence of muscle damage. These mice show a nonsense point mutation (C-to-T transition) in exon 23 leading to the absence of full-length dystrophin protein. The course of the disease in these mice is less severe than in humans, with only a 25% reduction in lifespan because severe muscle damage does not occur until the mice reach 15 months of age.

There have been several reports of PBMT being used to treat these mice and primary muscle cells derived from them in the laboratory. Huard et al. showed that exposure of primary mdx muscle cells to 830 nm at 5 J/cm² increased proliferation, increased antioxidant enzymes, decreased oxidative stress, and lowered inflammatory markers. ⁸ Albuquerque-Pontes et al. treated mdx mice on the tibialis anterior muscles with a cluster probe containing 904, 875 and 640 nm LEDs at 10 J per session 3 × /week for 14 weeks. Muscle performance, morphology, and the expression of dystrophin protein were significantly improved. ⁹ A follow-up study from the same group compared the above described PBMT protocol to treat mdx mice combined or not with prednisolone or ibuprofen. ¹⁰

All PBMT groups showed improvements in muscle performance, histological morphology, and dystrophin protein expression. The anti-inflammatory drugs did not make much overall difference. Macedo et al. treated mdx mice with 830 nm laser at 0.6 J/session on the quadriceps muscle 3 × /week for 2 weeks. ¹¹ The treated mice showed less muscle damage, along with lower levels of ROS and inflammatory markers.

If PBMT is investigated as an appropriate treatment for human DMD patients, how should the light be delivered? I believe that a whole-body light bed fitted with 660 and 850 nm LEDs would be an ideal choice, because this approach can deliver significant amounts of energy (tens or hundreds of kilojoules) across all major muscle groups. However, a large LED panel could be a more affordable alternative for home use, because PBMT may need to be used for the entire lifetime of the patient. Considering the lack of any adverse effects caused by LED PBMT, I believe that it is now time to conduct a pilot trial for DMD patients.

It was mentioned previously that caution should be exercised before using PBMT to treat hereditary diseases. ¹² The reason for this caution, is that PBMT could conceivably stimulate harmful pathological processes caused by the presence of mutated or missing proteins. However, I do not believe that this possibility exists in the case of DMD, because the beneficial effects of PBMT on mitochondria, stem cells, inflammation, and oxidative stress will take precedence over any adverse effects caused by abnormal dystrophin. Moreover, some animal experiments suggest that the expression of normal dystrophin could actually be increased by PBMT.